Use of thalidomide in the management of three HIV seroreactive children with Kaposi's Sarcoma referred for palliative care

Introduction

This is a description of three teenage children who were referred to Umodzi Paediatric Palliative Care service at Queen Elizabeth Central Hospital in Blantyre, Malawi with Kaposi's sarcoma (KS) in addition to HIV infection. These cases demonstrate the holistic approach of palliative care, addressing physical, psychological, social and spiritual aspects of patient care. They are also examples of very sick children who have responded well to antiretrovirals (ART) and thalidomide and show the effectiveness of good symptom control on quality of life.

Matthew

Matthew is a 14 year old boy who was first referred to the Paediatric Palliative Care Team in May 2008 due to severe cutaneous Kaposi's sarcoma, with heavily infected wounds and ulceration on his left leg below the knee for the past 5 days. He also had florid and extensive molluscum contagiosum all over his face.

On his background history, he was described as being unwell since the age of 8 years, and had been treated for tuberculosis 3 times, lastly for miliary TB in February 2007.

He was staged as eligible for ART at this time and started in March 2007 at QECH. However, he had continued to develop swelling and skin lesions on his left leg , which was diagnosed as KS and treated with 2 doses of vincristine in April/May.

At presentation, the leg was covered in sores which were oozing, malodorous and painful such that he was unable to walk. Topical gentian violet solution and crushed metronidazole tablets were applied. At review after 2 weeks, there was very little change; the left leg was still very swollen with open sores, and dressing changes were difficult as the bandages were so stuck down. This was causing considerable distress, so a dose of oral morphine, 5 mg in 5 mls, was given and his accompanying guardian was taught how to give this prior to dressing changes. Vaseline gauze was used, and dressings changed to alternate days.

Thalidomide 100mg at night (recommended dose 3mg/kg) was started for treatment of KS.

The following week, he was looking much better, both the leg and his face were improved and he seemed much happier in himself, so all treatment was continued. (figure 1)

Figure 1.

When he came for review after 2 weeks, he had developed headache. There was no associated fever, vomiting or convulsions, but he did report episodes of shaking and confusion. Cerebrospinal fluid examination with India ink staining indicated that he had developed cryptococcal meningitis and this was treated with fluconazole. He was distressed with the pain so morphine, 5mls of weak solution ie 5mg in 5ml four hourly was started. He had a good night and was pain free the following morning, and although not vomiting, he was nauseous so domperidone antiemetic was also given. During this time, the skin lesions on his face continued to improve, and his leg was also getting better and could now be left open and undressed.

The next day, his pain was consistently improved, and he was started on bisacodyl laxative prophylactically as morphine is constipating. Over the next 3 days he did report difficulty opening his bowels and gave a history of small amounts of fresh blood on the stool suggesting anal fissure so was advised to apply Vaseline to ease the discomfort of passing stool. However, he was much more alert and lively, sitting up in bed and eating well with no nausea or vomiting.

Morphine was stopped and he was changed to tramadol as a weak opioid, in accordance with the WHO analgesic ladder¹. Mobilisation was encouraged.

He continued to improve over the next few days, and was discharged on fluconazole, which he would need to continue long-term, ART, thalidomide, cocodamol and bisacodyl.

2 ½ weeks later, he was able to climb the stairs himself to come to our office. His left leg, which had been infected with cutaneous KS, was improving very well and no longer required topical treatment. He had no headache, no diarrhoea, vomiting, constipation or per rectal bleeding. His medication was continued.

The only sad change was that Matthew, whose parents had died in 2005, had now moved to live with his maternal uncle just outside Blantyre to the north, and where he was now living was too far to walk to school so he was no longer able to attend. We tried to encourage the family to rethink this arrangement as he had previously been doing well at school, and his prognosis on current treatment was now much better.

At review a month later, his left leg was much better and he was walking well. (figure 2)

Figure 2.

The only new complaint was of visual loss, dating back to his admission the previous June, ie 2 months earlier. There had been gradual deterioration with sparing of peripheral vision but he was significantly short sighted. He was able to recognise shapes, but could only read large print. The ophthalmologist had diagnosed optic atrophy, and told them no treatment was possible. He was no longer on Tuberculosis treatment but this could have been ethambutol related. He was a bright boy and had previously done well in school, in a family where education was a high priority, and both his current main carer, his uncle Mr. K, and the aunt who had previously cared for him and was a teacher, spoke fluent English. We discussed with Matthew, Mr. K and the team the educational possibilities for blind and partially sighted children, and investigating the resources at the Blind School at Ngaludi - about one hours drive from Blantyre. We subsequently obtained a magnifying glass with a reading light bulb, and found a couple of books with fairly large print for him, which his uncle collected.

Thalidomide was stopped as he had completed a 4 month treatment course. We saw him again a month later in mid-January, and were delighted to hear that he had started back at school. He has to walk 4 km to get there, which he was finding very tiring, but his uncle felt confident he can now manage this. He was managing to read and write with the help of the magnifying glass getting his school books photocopied in dark, large print to make it easier for him to use them was also discussed. There was no evidence of any recurrence of KS .

In summary, Matthew, who had been acutely ill with life-threatening complications of HIV infection on several occasions, is now in a phase where he is well and his quality of life is good. He seems well cared for and his uncle is trying to create opportunities for him. He needs to continue ART and fluconazole but there has been no sign of recurrence of Kaposi's sarcoma since completing thalidomide, now over one year ago. His palliative care needs are low at present and our role is mainly supportive.

Mark

Mark is a 15 year old boy referred in May 2006. He had been well until the beginning of that year, when he had developed painful skin lesions on his right upper lip, and on his left foot.

He had tested positive for HIV in February 2006 at QECH, and this was known by both Robert and his carer, who was his mother at that time. He had started Triommune ART at the end of April, and had also had a single dose of vincristine for the skin lesions, which had been diagnosed as KS.

His main concern at referral was a very sore mouth with ulcerated KS lesions on his tongue and lip, causing halitosis, difficulty eating and misery. This was initially treated with metronidazole mouthwash (made by combining 300mls water, 150mls concentrated orange juice and a crushed 200mg metronidazole tablet), ketoconazole, gentian violet paint topically to the lip lesion, and multivitamins. He was provided with straws to drink through and drawing materials to distract and cheer him up. He reported feeling better straight away after good mouth care, suggesting mouth pain and hunger were a major cause of his misery. The next day, his mouth was improving and he was drinking and eating, so he was discharged, planning to return for his second dose of vincristine the following Monday.

Unfortunately he defaulted so the 2 nurses on our palliative care team visited him at home 2 weeks later. They found he had missed clinic because he had been too unwell to attend, but had now improved. The sores in the mouth were no longer painful, but the foot wound was still troublesome and he complained of being hungry. Mouthwash and analgesics were restarted, and review was planned for 2 weeks time when he was due to attend the ARV clinic.He defaulted again but was brought a few days later, carried by his mother because of the pain from the KS lesion on his left foot. The ulcer on his tongue was deep and his mouth was very sore. The wound was dressed and metronidazole mouthwash was restarted. He was also given analgesics - ibuprofen, paracetamol and tramadol, which he had found effective previously. It is common practice in palliative care to add analgesics stepwise to achieve good pain control. His mother was told to come for more medication as required, and that she could come by herself if Mark was unable to walk. Over the next 4 months, he was reviewed periodically for analgesia and nutritional supplementation.

In February 2007, Mark presented with difficulty swallowing, with a sensation of pharyngeal blockage that he said had been there for several months but painless. His speech was unclear as his tongue was coated and there was evidence of oral candidiasis, and also extensive KS of the posterior part of the upper palate and tongue. He had already had a course of vincristine, which had not led to significant improvement, and the oncology team were not planning to repeat it, so thalidomide was started for treatment of KS. This also has a useful side effect of increased appetite and weight gain and his weight had dropped by a kilo in the previous 5 months. He was started on 100mg at night, with a view to continuing thalidomide for 3–4 months if he was tolerating it well. He was also given nystatin drops for oral candidiasis.

At review after 11 days, there had been good improvement in his swallowing, and both his tongue and palate looked clean and improved.

At one month review, we were delighted to note a good response to thalidomide and the tongue lesion was barely visible. He continued to do well on thalidomide, and this was stopped at the beginning of June. When he came back a month later for review at the ARV clinic, he was well and his tongue was clear, with no sign of active KS but a small area of scarring. He was eating well and had a good appetite, and was also now attending school again. The foot lesion was also healed.

This was a very positive visit, and Mark's quality of life had greatly improved since he was first referred over a year ago. It was however sadly the last time we saw him with his mother, as she died the following month after a short illness,thought to be meningitis.

He next came 3 months later, now aged 16 years and in year 7 at school. He said he was coping since the loss of his mother and his affect was good. He is now living with 3 of his brothers (he is the youngest in the family), none of whom have regular jobs. He attends school when well, but frequently misses weeks due to self limiting symptoms, such as headache, sore throat or abdominal pain. He was encouraged to take analgesics when necessary, and to continue to attend school when taking these.

On examination, he looked well, was growing well and there was no recurrence of the tongue or foot lesions and no sign of oral candidiasis He has been referred to an orphan care programme for financial and nutritional support. Again his palliative care needs have resolved for the time being, and he has adjusted well to his bereavement. Nearly 2 years since completion of the thalidomide course, there is no sign of any recurrence of KS but we will monitor this periodically.

He may have outgrown our paediatric service by the time he needs palliative care again, but we plan to stay in touch and offer ongoing support as needed for the present.

Martha

Martha is a 14 year old girl who lives with her father and sister as her mother died in 1997. She is the youngest of 6 siblings, the others all being reported as well. Her father is also well and works within the Department of Health.

She was referred to QECH from an Italian independent mission charity which provides an antiretroviral treatment programme. She was diagnosed with KS of the palate and buccal mucosa and started on Triommune ART in January 2007, but after 4 months on ART, there was no improvement in the palatal KS, and she also had anaemia and mild pedal oedema. She was admitted and started on vincristine, given as 3 doses one week apart. She received a blood transfusion and was referred to palliative care for pain management. She was discharged with instructions to return for the next dose of vincristine.

After one week, the tumour was already showing signs of regression, but Martha was complaining of burning pains in her feet as a side effect of vincristine, so amitriptyline was started, 12.5mg at night, and ibuprofen was continued for painful mouth.

Over the next 6 weeks, Martha's father came 4 times for more analgesia reporting she was having abdominal pains, and that she was coughing. On 2 occasions, he was asked to bring her to be examined, and eventually she was brought to hospital during the night with cough, pleuritic chest pain and numbness of the legs and admitted to the paediatric special care ward. Although she had previously been on amitriptyline, this had been stopped in the last few days, so was restarted. Investigation into the cause of cough and breathlessness revealed a blood-stained pleural effusion indicative of pulmonary KS and vincristine was restarted that day.

Over the next week, Martha continued to improve and was able to sit out of bed. However she was complaining of pain in her back and legs so gentle exercises and massage were advised, and amitriptyline and ibuprofen continued. The mouth lesions had reduced slightly and she was now eating well, so went home after the second vincristine dose, to return after a week for the third dose as an out patient. At this stage she was feeling well enough to play. She returned as planned for her third vincristine dose as an outpatient.

At the end of August 2007, Martha's father came to tell us that she was barely walking more than a few steps as she had continued to be breathless and had pain in her legs all the time. She was able to sleep at night, and was eating but vomiting occasionally. She was being looked after during the day by her 19 year old sister.

A home visit was carried out the following week to reassess Martha's situation, and to advise on physiotherapy and prevention of pressure sores as she now had such reduced mobility. Martha was comfortable and not distressed. The palatal KS had reduced further and she confirmed that she was eating well but she still complained of peripheral neuropathy causing pain in her feet and although it had initially improved on amitriptyline, this was no longer helping.

The other issue was dyspnoea, especially at night. She had been sleeping outside the house since her last discharge in order to benefit from the breeze, and had one pillow. On examination, there was bilateral inspiratory and expiratory wheeze in her chest, felt to be due to pulmonary KS.

The dose of amitriptyline was increased and a chest Xray requested when she next attended the ART clinic in a weeks time . Low dose morphine was not indicated for her dyspnoea as she was not distressed and non-pharmacological methods to reduce the discomfort of dyspnoea were effective.

Chest Xray appearances were consistent with pulmonary KS and thalidomide was started as vincristine now seemed unlikely to be beneficial as symptoms had recurred so soon after stopping the weekly doses. Obviously there were issues to consider in using thalidomide to treat an adolescent girl-even though Martha was small and underdeveloped for her age. The risk of severe fetal abnormality if used in pregnancy was explained to Martha's father, as well as the side effect of peripheral neuropathy, but he was keen we should start treatment and we had no other option to offer.

At 2 week review, Martha was sleeping well, with no pain, and her dyspnoea was improving. The following month, she was walking and playing, looking much better and no longer breathless. Her weight was down a bit, so she was also given food supplementation.

At the end of the month, she was reviewed again and was doing very well. The mouth lesions were greatly improved but a small area of KS remained on the right side of her upper palate and there was still an area with a bruised appearance anteriorly on the left side of the lower gum where the old lesion had been previously. Her weight had increased, and continued to improve. Thalidomide was stopped after she had completed 3 ½ months treatment. On chest examination, her breathing was normal and the chest was clear. Her mouth was also completely clear, and she said she was eating well. She looked anaemic and the last haemoglobin measurement was 8.1g/dl, so her PCV will be monitored, but otherwise, we were very pleased with her condition. She was also attending school, in Standard 7, and looked well and happy.

Again, this child has responded very well and is currently well 10 months after stopping thalidomide. We explained that the thalidomide may not be a cure but can alleviate symptoms for some time, and can be restarted if symptoms of KS recur.

Thalidomide Discussion

Thalidomide is infamous for its association with severe fetal abnormalities -particularly limb deformities, which can occur with only one dose in early pregnancy. However, it is now well recognised in the treatment of KS, as well as HIV-associated wasting, severe aphthous ulcers and HIV related diarrhoea². It works by inhibiting tumour necrosis factor - a cytokine associated with the development of aphthous ulcers, dementia, fevers, fatigue and wasting and enhanced HIV replication³, and has also been shown to be effective in the treatment of both non-HIV⁴, and HIV-associated KS⁵.

There is no radiotherapy available in Malawi, and first line chemotherapeutic treatment at QECH paediatrics department is vincristine, but we have found 3–4 month courses of thalidomide effective in treating KS, in conjunction with ART and where KS has progressed despite treatment with vincristine. There is evidence that more long term use is also safe and effective⁶, with appropriate safeguards to prevent teratogenicity. It is essential to counsel patients and guardians, to ensure female patients are not pregnant and abstain from sexual intercourse or use two forms of effective contraception; and to advise male patients to abstain from sexual intercourse or use a condom. This is in accordance with the System for Thalidomide Education and Prescribing Safety program (STEPS)⁷. In HIV disease, the other side-effects of sedation, increased appetite, weight gain and constipation may actually be beneficial; peripheral neuropathy, which is more common in women and older people, is a more serious side-effect and requires vigilance as it can be irreversible⁸, but the cause of peripheral neuropathy may be difficult to decipher in polypharmacy, as ART, vincristine and HIV itself can all cause this.

Thalidomide is currently expensive at $5 per 100mg tablet, $500 for a course of treatment, but is a single oral daily dose and does not require hospital stay or expensive investigations. Further study into the cost effectiveness is warranted, but our clinical experience suggests that thalidomide has a useful role in the treatment of KS in children.